You need phasic, firing and "burst" activity of monoamines, SSRI's supress that releasing agents dont, there are ways to reverse it again or increase burst activity of monoamines tough (looking into it atm will post more later)

Neurokinin-1 (NK1) receptor antagonists have been reported to possess antidepressant and anxiolytic properties in controlled trials. Since antidepressant and anxiolytic drugs act mainly by enhancing serotonin (5-HT) and norepinephrine (NE) neurotransmission in forebrain areas, the main focus of the present review is to critically examine the electrophysiological effects of NK1 receptor antagonists on serotoninergic and noradrenergic neurons, and then hippocampal neurons. It is concluded that NK1 antagonists increase the firing and burst activity of 5-HT neurons, increase burstactivity of NE neurons, and modulate postsynaptic transmission at the hippocampus level. Further research is needed in order to develop more selective ligands for the human NK1 receptor and to gain better knowledge of required brain penetration and optimal pharmacodynamic conditions for their use in patients.

Just checking in again to this thread to see if I can figure things out, if the Wellbutrin I'm taking doesn't seem to hit this thing. Glad though that I'm on the right track.

The most effective med for me EVER was olanzapine - not feasible for me long term, but very effective. There was a lot of talk about I think how bad quetiapine is for anhedonia, and I wonder why olanzapine would work so differently. Does anyone know a good website listing different meds affinities for various receptors?

I see a lot of people on here get very excited about selegiline due to its dopaminergic action, although I don't know if it was mentioned in this thread yet. I was on the highest dose transdermal patch (Emsam) for several months - in fact I may have even been over the highest patch and was halving additional ones at my doctor's advice (I believe something like 15mg total if I'm remembering correctly). Anyway, although I felt that it helped very slightly in some respects (but not really so much in terms of anhedonia), I came to a point where I felt like I plateaued and couldn't get any further benefit out of it. I don't know how much more or less effective it would have been orally, but at least what I was doing didn't work for me..

I read about agomelatine earlier in this thread - interesting because I've never heard of it before it says it's similar to melatonin. That made me think of 5-HTP, which is a precursor to melatonin, so I wonder if there are any similarities? Although I guess 5-HTP has been touted as a bit of a "natural SSRI", and it's been said in this thread (and in my personal experience as well) that those are no good for anhedonia. In addition, does anyone know if the affinities for inositol are helpful? I can and have searched for 5-HTP and inositol along with the binding sites listed in this thread ( 5ht2a, 5ht2c) but I'm really not well versed in the area in order to interpret random results that I get. However, if they do have affinities for those receptors it may be helpful for some to try as an easy OTC option.

I tried inositol and 5-HTP a few months ago, and I think they actually helped, but due to anticipating a med change and fear of serotonin syndrome I stopped the 5-HTP, and I was never able to work up to a dose of inositol that didn't give me terrible diarrhea...

2. Selective Serotonin Reuptake EnhancerSSRIs only worsen the anhedonia, which makes the SSRE a candidate worth trying. Unfortunately Tianeptine is only available in some countries, but I believe people who've suffered years can go to great lengths to try potential treatments.

3. AdaptogensAdaptogens probably won't do very much for depression, but because they're easy and safe to use, they're worth trying. They can also be co-administrated with other choices of treatment and they may enhance their working. Rhodiola Rhosea seems to be perhaps the most common choice, but Echinacea Purpurea also seems to have many qualities that could possibly be anti-anhedonic. Nearly all true adaptogens seem to contain at least some mild anti-depressive features when tested with rodents.

4. Quetiapine

There is no solid evidence on Quetiapine actually working on anhedonia or depressive attention deficiency and it is also a dopamine antagonist. However its antagonism for the serotonin receptors 1A and 2A is something noteworthy.]

Ldopa wont help as anhedonia has little to do with DA.

Tianeptine wont help either, nor do i see any mechanism behind adaptigens wich can help.

Seroquel DEF wont help at all, 5HT1A antagonism i cant see be of any help, besides its metabolitite is a partional 5HT1A agonist, 5HT2A agonists most likely help (low treshold doses of psychedelics abolish anhedonia,

Can you show me where you got 5HT1A antagonism from? I can only find studies showing it being a partial agonist.

Just checking in again to this thread to see if I can figure things out, if the Wellbutrin I'm taking doesn't seem to hit this thing. Glad though that I'm on the right track.

The most effective med for me EVER was olanzapine - not feasible for me long term, but very effective. There was a lot of talk about I think how bad quetiapine is for anhedonia, and I wonder why olanzapine would work so differently. Does anyone know a good website listing different meds affinities for various receptors?

I see a lot of people on here get very excited about selegiline due to its dopaminergic action, although I don't know if it was mentioned in this thread yet. I was on the highest dose transdermal patch (Emsam) for several months - in fact I may have even been over the highest patch and was halving additional ones at my doctor's advice (I believe something like 15mg total if I'm remembering correctly). Anyway, although I felt that it helped very slightly in some respects (but not really so much in terms of anhedonia), I came to a point where I felt like I plateaued and couldn't get any further benefit out of it. I don't know how much more or less effective it would have been orally, but at least what I was doing didn't work for me..

I read about agomelatine earlier in this thread - interesting because I've never heard of it before it says it's similar to melatonin. That made me think of 5-HTP, which is a precursor to melatonin, so I wonder if there are any similarities? Although I guess 5-HTP has been touted as a bit of a "natural SSRI", and it's been said in this thread (and in my personal experience as well) that those are no good for anhedonia. In addition, does anyone know if the affinities for inositol are helpful? I can and have searched for 5-HTP and inositol along with the binding sites listed in this thread ( 5ht2a, 5ht2c) but I'm really not well versed in the area in order to interpret random results that I get. However, if they do have affinities for those receptors it may be helpful for some to try as an easy OTC option.

I tried inositol and 5-HTP a few months ago, and I think they actually helped, but due to anticipating a med change and fear of serotonin syndrome I stopped the 5-HTP, and I was never able to work up to a dose of inositol that didn't give me terrible diarrhea...

Zyprexa (with prozac) is known to help anhedonia, im not sure about the mao.

2. Selective Serotonin Reuptake EnhancerSSRIs only worsen the anhedonia, which makes the SSRE a candidate worth trying. Unfortunately Tianeptine is only available in some countries, but I believe people who've suffered years can go to great lengths to try potential treatments.

3. AdaptogensAdaptogens probably won't do very much for depression, but because they're easy and safe to use, they're worth trying. They can also be co-administrated with other choices of treatment and they may enhance their working. Rhodiola Rhosea seems to be perhaps the most common choice, but Echinacea Purpurea also seems to have many qualities that could possibly be anti-anhedonic. Nearly all true adaptogens seem to contain at least some mild anti-depressive features when tested with rodents.

4. Quetiapine

There is no solid evidence on Quetiapine actually working on anhedonia or depressive attention deficiency and it is also a dopamine antagonist. However its antagonism for the serotonin receptors 1A and 2A is something noteworthy.]

Ldopa wont help as anhedonia has little to do with DA.

Tianeptine wont help either, nor do i see any mechanism behind adaptigens wich can help.

Seroquel DEF wont help at all, 5HT1A antagonism i cant see be of any help, besides its metabolitite is a partional 5HT1A agonist, 5HT2A agonists most likely help (low treshold doses of psychedelics abolish anhedonia,

Can you show me where you got 5HT1A antagonism from? I can only find studies showing it being a partial agonist.

In combo with a SSRI partional agonism will raise sero and act as an antagonist otherwise more of a agonist but not sure about its intrinsic actvity, mostly relates to buspar.I didnt refer to seroquel

Can anyone help me get started on Phenibut? I've got some, but they're in capsule form and I've been taking pitifully low doses due to fear of tolerance and side effects. What kind of dose should I be looking for to help with anhedonia and how is it best taken to avoid tolerance and withdrawal?

What's the half-life like, and how soon after the dose should I expect effects? Is it something that you build up to or more immediate? It would probably not be worth trying if I'm feeling relief half the week - looking for something more stable and constant.

Also, can you point out what specifically pharmacologically about the Zyprexa that indicates its usefulness in anhedonia? I noticed you didn't really mention any other antipsychotics other than Amisulpride, which I can't get in the US. Certainly all the atypicals work on dopamine to some extent, was it just that olanzapine happened to have the study backing it?

Also, yes, it has terrible side effects. But I may have to end up getting on it again. Speaking of terrible side effects, I've always wondered about clozapine, since it's structurally similar. I remember reading about the case of a highly schizophrenic child who ONLY responded to clozapine, so I'm assuming they tried olanzapine etc. beforehand.

interesting stuff, because in my experience that's been true with the olanzapine - tried almost every other atypical out there, although not clozapine due to the blood monitoring etc.

Does the methoxetamine exhibit the same effects that people talk about with ketamine for very rapid relief of depressive symptoms? That's also a route I haven't tried, because I haven't found any doctors who are good enough to prescribe or administer things like that.

I have retrograde amnesia from ECT so I can't give specifics, but I do know historically that the only medication that really gave me any kind of relief from depression was starting on a low dose of zyprexa (2.5) as a teenager. I'm assuming it helped everywhere across the board with depressive symptoms, including anhedonia. I tried to go off of them for a while but got terrible somatic effects, similar to how my depression manifested itself as a child. I believe it's what got me through college, but from what I understand, a few years ago it started pooping out, and the dose was increased to compensate. Since I was on the low dose, I was never really hit by the side effects, but they got pretty bad and I gained about 20 pounds in a very short time.

I have been off of meds for a 4-5 month period to try alternative methods, to gauge their efficacy and give my brain a chance to reset after having been constantly on meds for the past 10 years...I'm not against meds, but if another less harsh method could be used with supplements etc., I'm all for it.

Whoops, is this thread strictly for people with anhedonia without depression? Apologies. But I am a big non-responder when it comes to meds, so I often really question the nature of what's going on with me.

I have dealt with anhedonia all while growing up, but it wasn't a sad, depressive anhedonia. It was more of a "perpetually bored" type of thing. I was always content with this until my college years. I tried to go to school for computer engineering at one of the top schools in the country. Even though I was naturally gifted, I had no drive or motivation to do my school work. Once the novel nature of a subject wore off, so also did my ability to focus on the subject.

After failing numerous times and switching schools, the rejection started to cause anxiety (which I had never experienced in my life). Then, my girlfriend of 5 years cheated on me. I guess some psych docs would say that I had PTSD type symptoms from this. Combine this with the underlying anhedonia, and you have a recipe for disaster. At this point, I pretty much just slept and tried to find things to amuse myself, accomplishing nothing but wracking up credit card debt as I foolishly tried to still attend school. I gradually worked my way out of the depression, insomnia, and the majority of the other symptoms related to a really bad heartbreak. But I still couldn't pass classes or pay attention. It was like my anhedonia had increased 10 fold.

I finally went to see my doctor. He prescribed me adderall. My anhedonia disappeared, but I had every side effect of amphetamines. My BP went ridiculously high too. After about 6 months of this, I quit school, quit adderall, and starting studying the brain.

I spent more money then I could ever afford on nootropics and supplements, and spent months researching. Then, I started taking the CILTEP stack before Abelard Lindsay even posted it publicly. I noticed a change in my brain, which was one of the first times I actually felt anything from any "noots" or supplements (with the except of methylcobalamin which caused euphoria for several days when I first started taking it). But I still was getting nothing done. In frustration, I went back to the doctor, and got a script for Adderall (this was about a year after I had stopped). I also decided to try Selegiline, in order to hopefully reduce the dosage of Adderall. Because of the contraindication between the 2, I decided to start out very small. 5mg of each.

From the very first day, my brain fired up and started working again. Similar to when I had previously adderall (at a much higher dosage), without the tunnel vision and side effects. I was amazed... shocked... I had my life in my control all of a sudden. I told the doctor how excited I was. He was shocked and amazed. He even stopped worrying about the possible interaction, since I was taking such low doses.

Did I mention I never stopped taking CILTEP during this trial? Because I kind of forgot this small detail at the time. I starting noticing massive amounts of productivity on some days, yet none on others. These productive days always "happened" to fall on days which I took artichoke and forskolin along side of my selegiline and adderall. I started playing with the doses and found that I didn't even need the Selegiline. I also needed 1/4 of the forskolin dose I was taking.

That is the story of how I stumbled upon the stack that saved my life. Fast forward to 8 months later: I'm getting married in three months; I have my own business; and I have an interview for a part time job tomorrow. I'm anhedonia free, and with a few tweaks to the original regimen, I feel healthier than ever. Of course, if I ever miss a day, I'm right back to my usual self (which is nice for relaxing on vacation!).

The important part of this whole thing is to note that I was never chemically depressed or anxious for no reason, which is why I never entertained the ideas of SSRI's. My depression and anxiety came from the real life consequences of a lifelong struggle with anhedonia. Once I was able to conquer anhedonia, the hopelessness dissolved, and with it so did any lingering depression and anxiety.

It's very important to be able to get to the root of the problem if you are ever going to defeat it. I've never been able to quite pin down the exact cause of my issue (though I've entertained several theories), but it's clear that I am either too stongly influenced by one of the inhibitory neurotransmitters, or not enough by one of the excitatory ones. I still continue my search, but at least I am enjoying life and accomplishing my goals while I continue to expand my knowledge about the human brain.

Zrbarnes: you do not use any tolerance prevention techniques whatsoever, short of using forskolin/artichoke to increase the potency of your adderall? Do you cycle adderall whatsoever? I've always been hesitant to consider stimulants as a long-term solution due to the issues with tolerance, always hoping that there were a way to upregulate dopamine.

Forskolin upregulates D2 like nmda antagonists and could perhaps act as a tolerance preventor.

Whoops, is this thread strictly for people with anhedonia without depression? Apologies. But I am a big non-responder when it comes to meds, so I often really question the nature of what's going on with me.

Would tricyclics have the same inherent problem as SSRIs?

It wasnt but depression induces it and the pharmacology behind it is usually diff.

So you take selegiline, cilltep and adderall and the addition of sele made a massive difference?

Here is how it went down:

-I took Adderall (20mg, twice a day) for 6-8 months - terrible side effects, quick tolerance, crash every night.-I took a break for almost a year.-I took Selegiline (10mg/day) for 2 months - slightly improved focus and anhedonia, but some days it was comparable to placebo.-I started taking Selegiline (10mg/day) + Forskolin + Artichoke for a month - same improved focus and anhedonia, but also a shift in perception. It's hard to describe. It did however greatly potentiate caffeine, which is why I kept taking it.

-The crazy results persisted when I removed Selegiline. However, if I remove adderall, forskolin, or artichoke for a day, those results go away for that day.

This stack worked for a couple months before I started getting sleepy everyday. I fleshed out a pretty good theory that it was caused by nAChR desensitization from the Forskolin (I posted the research over in the CILTEP thread). In order to prevent this from happening, I picked up some 98% forskolin extract (instead of the 20% I was taking), and dropped my dose down to 5-10mg a day. I also picked up some Galantamine from SmartPowders. I take 8mg on my non-adderall days (about one or two every couple weeks).

My current stack:

I've been on CILTEP + adderall for ~6 months with no tolerance. This current iteration has been stable for a month, with no signs of tolerance.

I wake up in the morning, and take 200mg sublingual Uridine 5 monophosphate, first thing. After about 15 minutes, I take 10mg forskolin, 1 artichoke extract pill, 200mg of quercetin, and 5mg of Adderall.

Since I still have a bunch of Selegiline, I started taking it about 1mg a day with lunch. I also take some omega-3 at this time. Before bed, I take 3mg of time released melatonin, and magnesium l-threonate.

If I ever get too stimulated and get a little irritable (not too often, usually only if I drink an energy drink), I take about 100mg of l-theanine. I also never redose forskolin or adderall. Every time I've tried this, I feel terrible.

About 12 hours after I take the Forskolin, I start to get sleepy. Not a huge crash like when I was taking only adderall, but more of a "Hey, it's time for bed." Caffeine can help with this if I need to keep going, but it actually works out pretty well for me. I've been an insomniac my whole life, so for the first time in my life, I actually feel like going to bed at a decent time.

Anyway, it took a lot of trial and error to get to this point, so I'm sure my experiences/doses can't just be copied and pasted onto the next guy. But I had almost gave up hope of ever being able to function correctly without using lots of Adderall and eventually having a heart attack.

A quick note about Adderall:

I'd like to switch to dextroamphetamine, just to get rid of that pesky 1.25mg of l-amphetamine (adderall is 25% l-amphetamine) I have to take daily that likes to bump up my blood pressure a bit. Not nearly as bad as when I was taking larger doses, but I don't want it at all. Without CILTEP, Adderall worked better than d-amp. With CILTEP, d-amp works great and with fewer side effects.

A quick note about other supplements:

I also take sublingual methylcolabalamin, methylfolate, p5p, and potassium on random days, when I remember. They aren't "necessary" to the stack, but they seem to work well, so I keep them around. Same thing with everything else I listed above. Adding Uridine, Selegiline, and Quercetin seems to help balance out the stack to a more positive, social mood, and helps it to last about 12 hours instead of 6-8.

But the staple stack that always works without fail is forskolin, artichoke, and adderall.

There's an excellent review article that medievil posted recently that discusses some preliminary treatment options. In my experience, and based on the literature, most anhedonia is primarily anticipatory in character. In that case, dopamine reuptake inhibition or agonism (without dopamine downregulation) is desirable. The only commonly used DRI (actually an NDRI) is wellbutrin.

Wellbutrin is primarily an NRI, it's Dopamine share is rather weak (I certainly never felt any real dopaminergic effects from it). The most commonly used DRI is actually, wait for it, Ritalin. Trying to brow beat my shrink into giving me a prescription for that (not that it is particularly hard to obtain without but hey, let health insurance pay for it , ultimately I fit some of the symptoms of ADHD-PI so quite aside the Anhedonia, it would be worth a try.

So you take selegiline, cilltep and adderall and the addition of sele made a massive difference?

Here is how it went down:

-I took Adderall (20mg, twice a day) for 6-8 months - terrible side effects, quick tolerance, crash every night.-I took a break for almost a year.-I took Selegiline (10mg/day) for 2 months - slightly improved focus and anhedonia, but some days it was comparable to placebo.-I started taking Selegiline (10mg/day) + Forskolin + Artichoke for a month - same improved focus and anhedonia, but also a shift in perception. It's hard to describe. It did however greatly potentiate caffeine, which is why I kept taking it.

-The crazy results persisted when I removed Selegiline. However, if I remove adderall, forskolin, or artichoke for a day, those results go away for that day.

This stack worked for a couple months before I started getting sleepy everyday. I fleshed out a pretty good theory that it was caused by nAChR desensitization from the Forskolin (I posted the research over in the CILTEP thread). In order to prevent this from happening, I picked up some 98% forskolin extract (instead of the 20% I was taking), and dropped my dose down to 5-10mg a day. I also picked up some Galantamine from SmartPowders. I take 8mg on my non-adderall days (about one or two every couple weeks).

My current stack:

I've been on CILTEP + adderall for ~6 months with no tolerance. This current iteration has been stable for a month, with no signs of tolerance.

I wake up in the morning, and take 200mg sublingual Uridine 5 monophosphate, first thing. After about 15 minutes, I take 10mg forskolin, 1 artichoke extract pill, 200mg of quercetin, and 5mg of Adderall.

Since I still have a bunch of Selegiline, I started taking it about 1mg a day with lunch. I also take some omega-3 at this time. Before bed, I take 3mg of time released melatonin, and magnesium l-threonate.

If I ever get too stimulated and get a little irritable (not too often, usually only if I drink an energy drink), I take about 100mg of l-theanine. I also never redose forskolin or adderall. Every time I've tried this, I feel terrible.

About 12 hours after I take the Forskolin, I start to get sleepy. Not a huge crash like when I was taking only adderall, but more of a "Hey, it's time for bed." Caffeine can help with this if I need to keep going, but it actually works out pretty well for me. I've been an insomniac my whole life, so for the first time in my life, I actually feel like going to bed at a decent time.

Anyway, it took a lot of trial and error to get to this point, so I'm sure my experiences/doses can't just be copied and pasted onto the next guy. But I had almost gave up hope of ever being able to function correctly without using lots of Adderall and eventually having a heart attack.

A quick note about Adderall:

I'd like to switch to dextroamphetamine, just to get rid of that pesky 1.25mg of l-amphetamine (adderall is 25% l-amphetamine) I have to take daily that likes to bump up my blood pressure a bit. Not nearly as bad as when I was taking larger doses, but I don't want it at all. Without CILTEP, Adderall worked better than d-amp. With CILTEP, d-amp works great and with fewer side effects.

A quick note about other supplements:

I also take sublingual methylcolabalamin, methylfolate, p5p, and potassium on random days, when I remember. They aren't "necessary" to the stack, but they seem to work well, so I keep them around. Same thing with everything else I listed above. Adding Uridine, Selegiline, and Quercetin seems to help balance out the stack to a more positive, social mood, and helps it to last about 12 hours instead of 6-8.

But the staple stack that always works without fail is forskolin, artichoke, and adderall.

Cheers mateShame i ran out of forskolin, it did induce ocd but st johns wort witch removed my ocd managed to block that i think needed to do some more experimenting.

nefiracetam slows morphine tolerance due to increased cAMP, forskolin also upregulates D2 due to that like nmda antagonists i dont find it suprising that forskolin may work for tolerance like zrbarnes with he's consistent effiacy.

Big doses of Nefiracetam (1g) kind of feels a lot of ways similar to the forskolin + artichoke + adderall combo. It is really the only thing that comes close for me.

Sadly, the majority of the effects seemed to only last 4-6 hours, and redosing too late in the day would leave me awake all night.

Also, there is always the testicle issue. No matter how well it works, it's still scary to take. Medievil posted a way to hopefully block the testicle toxicity from happening, I think, but it would be nice to see it tried on some animals, since I haven't had kids yet

Have you still have some? perhaps throw in the stack in a tiny dose of 100mg?

That idiotic company patented it for post traumatic apathy only while it has massive potential for other things, tried to get in touch with them to discuss other uses, if they didnt i would have patented it for shizophrenia (somehow.. i dont have any knowledge behind patents).

Just checking in again to this thread to see if I can figure things out, if the Wellbutrin I'm taking doesn't seem to hit this thing. Glad though that I'm on the right track.

The most effective med for me EVER was olanzapine - not feasible for me long term, but very effective. There was a lot of talk about I think how bad quetiapine is for anhedonia, and I wonder why olanzapine would work so differently. Does anyone know a good website listing different meds affinities for various receptors?

I see a lot of people on here get very excited about selegiline due to its dopaminergic action, although I don't know if it was mentioned in this thread yet. I was on the highest dose transdermal patch (Emsam) for several months - in fact I may have even been over the highest patch and was halving additional ones at my doctor's advice (I believe something like 15mg total if I'm remembering correctly). Anyway, although I felt that it helped very slightly in some respects (but not really so much in terms of anhedonia), I came to a point where I felt like I plateaued and couldn't get any further benefit out of it. I don't know how much more or less effective it would have been orally, but at least what I was doing didn't work for me..

I read about agomelatine earlier in this thread - interesting because I've never heard of it before it says it's similar to melatonin. That made me think of 5-HTP, which is a precursor to melatonin, so I wonder if there are any similarities? Although I guess 5-HTP has been touted as a bit of a "natural SSRI", and it's been said in this thread (and in my personal experience as well) that those are no good for anhedonia. In addition, does anyone know if the affinities for inositol are helpful? I can and have searched for 5-HTP and inositol along with the binding sites listed in this thread ( 5ht2a, 5ht2c) but I'm really not well versed in the area in order to interpret random results that I get. However, if they do have affinities for those receptors it may be helpful for some to try as an easy OTC option.

I tried inositol and 5-HTP a few months ago, and I think they actually helped, but due to anticipating a med change and fear of serotonin syndrome I stopped the 5-HTP, and I was never able to work up to a dose of inositol that didn't give me terrible diarrhea...

I would probably avoid agomelatine. The French drug company Servier just revealed that Valdoxan is very bad for the liver.